This application seeks five year funding for the K-23 Award: Patient-Oriented Research Career Development. The principal investigator, Ikechukwu I. Ekekezie, M.D., is currently Assistant Professor of Pediatrics, University of Missouri-Kansas City School of Medicine, Attending Neonatologist, Children's Mercy Hospital, Kansas City. The mentor for this proposal is William E. Truog, M.D., Professor of Pediatrics, University of Missouri Kansas City School of Medicine. The overall objective of this proposal is to provide the necessary support for the evolution of Dr. Ekekezie's career from that of a new productive investigator into an independent physician scientist investigating pathogenesis and treatment of chronic lung disease of prematurity. The application brings together three elements: 1) an able and active clinician-candidate for research career development (Dr. Ekekezie); 2) a superb physical and intellectual environment for clinical and applied research; and 3) the most common, but poorly understood, neonatal pulmonary disorder remaining: chronic lung disease of prematurity (CLD). The improvement in mortality afforded by prenatal corticosteroid and by post-natal surfactant therapy has increased the prevalence of CLD. No current therapy, such as anti-elastase or antioxidant therapy, appears to reduce significantly the severity of CLD. Comprehensive understanding of its pathobiology is lacking. Dr. Ekekezie is currently investigating the use of inhaled nitric oxide to ameliorate CLD. He has a supplement to R-01 HL58125, which has funded his studies examining inflammation and matrix injury in CLD. He has helped design a complex clinical trial as a proposed Co-Investigator for a trial currently under review (R-01 HL62514). He has developed expertise in the biology of extracellular matrix proteins including laminin, and in pro-inflammatory cytokines and their contribution to the evolution of CLD. The clinical study proposed for this application is to examine the disruption of the basement membrane and extracellular matrix by metalloproteinases (MMPs) in CLD and to examine the effects of nitric oxide and corticosteroid therapy on MMP activity in CLD. Therapy with anti-MMP agents may then be studied. Appropriate use of potential new therapies will necessitate evaluation of timing, dosage, side effects, and interactions with concomitant therapies. The often unhappy history of therapeutics in neonatology demands that the most critical thinkers available use their skills in the application of new treatments to sick newborn infants. The investment in Dr. Ekekezie represented by this Award - coupled with his own enthusiasm, skills, intelligence, and high oral standards -- ought to result in his being propelled into the next generation leadership group in this area. The K-23 Award mechanism is an ideal way to advance him from here to there.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL004264-02
Application #
6183152
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
1999-09-07
Project End
2004-08-31
Budget Start
2000-09-22
Budget End
2001-08-31
Support Year
2
Fiscal Year
2000
Total Cost
$124,850
Indirect Cost
Name
Children's Mercy Hosp (Kansas City, MO)
Department
Type
DUNS #
City
Kansas City
State
MO
Country
United States
Zip Code
64108
Zhang, Xiaoming; Reinsvold, Patrick; Thibeault, Donald W et al. (2005) Responses of pulmonary platelet-derived growth factor peptides and receptors to hyperoxia and nitric oxide in piglet lungs. Pediatr Res 57:523-9
Ekekezie, Ikechukwu I; Thibeault, Donald W; Simon, Stephen D et al. (2004) Low levels of tissue inhibitors of metalloproteinases with a high matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio are present in tracheal aspirate fluids of infants who develop chronic lung disease. Pediatrics 113:1709-14
Auten, Richard L; Ekekezie, Ikechukwu I (2003) Blocking leukocyte influx and function to prevent chronic lung disease of prematurity. Pediatr Pulmonol 35:335-41
Thibeault, Donald W; Mabry, Sherry M; Ekekezie, Ikechukwu I et al. (2003) Collagen scaffolding during development and its deformation with chronic lung disease. Pediatrics 111:766-76
Ekekezie, Ikechukwu I; Thibeault, Donald W; Rezaiekhaligh, Mohammad H et al. (2003) Endostatin and vascular endothelial cell growth factor (VEGF) in piglet lungs: effect of inhaled nitric oxide and hyperoxia. Pediatr Res 53:440-6
Truog, William E; Pallotto, Eugenia; Clark, Perry et al. (2002) Interaction of endogenous endothelin-1 and inhaled nitric oxide in term and preterm infants. Clin Sci (Lond) 103 Suppl 48:294S-297S
Thibeault, D W; Mabry, S M; Ekekezie, I I et al. (2000) Lung elastic tissue maturation and perturbations during the evolution of chronic lung disease. Pediatrics 106:1452-9